Promotion of rare nucleobase tautomers by metal binding

Abstract

Metal binding to ligands with the potential of existing in different tautomeric structures can dramatically alter the tautomeric equilibrium by stabilizing a particular, frequently minor, tautomer. The assumption that metal complexation of a minor tautomer is chemically irrelevant because of its very low abundance is misleading and in many cases wrong. In fact, from available X-ray structural data on metal–nucleobase complexes it is evident that metal binding to rare, as opposed to preferred tautomers, is anything but an exception. This “promotion of rare tautomers” through metal coordination is of particular biological relevance in the case of nucleobases because any deviation from Watson–Crick base pairing is potentially mutagenic. In recent years models of “metal-stabilized rare nucleobase tautomers” have been characterized for all common DNA nucleobases, including by X-ray crystallography. Though metal binding causes relatively minor structural changes in the nucleobases, electronic changes as expressed by acid–base properties, for example, can be substantial. In this perspective article the biological consequences of the occupation of nucleobase sites by a metal entity and the altered acid–base chemistry of the nucleobase with regard to base mismatch formation, prevention of base pairing, and acid–base catalysis in nucleic acids are examined. Although not relevant to biology, the behaviour of the unsubstituted parent nucleobases is illuminating in this respect and therefore included.